Project Summary Despite significant progress in diagnostic and therapeutic strategies and promotion of a healthy life-style, cardiovascular diseases including atherosclerotic coronary heart disease remain the primary cause of morbidity and mortality in the USA. The main focus of the current proposal is to test insulin-like growth factor I (IGF1) as an anti-atherosclerotic therapy in a pig model and to understand mechanisms underlying plaque- stabilizing effects of IGF1. We have shown that IGF1 reduced atherosclerotic plaque burden and promoted plaque stability in Apoe-/- mice. Recently we have identified LARP6, a collagen mRNA binding protein as a critical mediator of IGF1-dependent collagen I upregulation and increased mature fibril formation in smooth muscle cells (SMC). We hypothesize that LARP6 mediates IGF1-induced plaque stabilization effects and we will test this hypothesis in Specific Aim 1. Recombinant human IGF1 is FDA approved only for long-term treatment of growth failure in children with severe primary IGF1 deficiency. Confirmation of our murine studies in a large animal model will be critical to consider use of IGF1 to treat atherosclerosis in humans. We propose to test IGF1 effects on atherosclerotic plaque in Rapacz familial hypercholesterolemic (FH) swine in Specific Aim 2. We propose the following specific aims: Specific Aim 1: Demonstrate that LARP6 regulates collagen type I expression, fibril formation and deposition in atherosclerotic plaques, thereby enhancing features of plaque stability. We have created an inducible and conditional transgenic mouse model, in which LARP6 is overexpressed specifically in SMCs upon tamoxifen administration. We will assess atherosclerotic burden and features of plaque stability in this model. We will study mechanisms of IGF1-induced LARP6 upregulation focusing on the role of microRNAs. Specific Aim 2: To demonstrate that IGF1 reduces atherosclerotic plaque burden and promotes features of stable plaque in a swine model. Pilot data show the onset of complex lesions in FH swine coronary arteries that closely resemble advanced human atherosclerotic lesions. Our translational study will test the effect of IGF1 on atherosclerotic plaque burden and biology in high-fat diet fed FH swine, using serial coronary angiography and intravascular ultrasound, as well as post-mortem coronary artery analysis. We will demonstrate that IGF1 reduces atherosclerotic burden and increases plaque stability in pigs and to provide insight into mechanisms. Overall, our goal is to demonstrate the feasibility of using IGF1 as a novel therapeutic strategy to treat atherosclerosis. We anticipate showing that SMC-specific increase in LARP6 will mimic IGF-1 effects on plaque stability in mice and possibly reduce overall plaque burden and that a systemic increase in IGF1 will suppress atherogenesis and increase plaque stability in pigs. Either approach will be highly clinically relevant and lead to the development of innovative anti-atherosclerotic therapy.